Ocular iontophoresis typically involves the application of an electrical source to propel charged and/or active molecules from a reservoir into the intraocular tissues of a mammal, including a human or an animal. Positively charged ions can be driven into the ocular tissues by electro-repulsion at the anode while negatively charged ions are repelled from the cathode. The simplicity and safety of iontophoretic application includes enhanced targeted delivery of compound(s) of interest, and the reduction of adverse side effects have resulted in extensive use of iontophoresis in laboratory, clinical research and commercial use.
Unlike ocular injections (intravitreal, retrobulbar, subconjunctival and peribulbar) and intraocular implants, iontophoresis is a noninvasive technique used to deliver compounds of interest into the anterior and/or posterior compartments of the eye. Iontophoretic delivery can be used to obtain intraocular concentrations and residence times that are equal to or greater than those achieved by conventional modalities such as topical drops, ointments, and gels.
Iontophoresis has been widely used in dermal applications in which therapeutic compounds are transported across a patient's skin using electrical currents. Due to the relative high impedance of the skin, the electrical currents are generally relatively low. Consequently, dosage times tend to be relatively long, for example being greater than an hour. In such applications, iontophoresis can be applied to the patient's skin with an active drug-containing adhesive patch.
Ocular iontophoresis devices are typically constituted by a direct current (DC) electric field source coupled to two electrodes, referred to respectively as “active” and “passive” electrodes. The active electrode provides an electromotive force, when energized, that acts on an electrolyte containing therapeutic composition(s) to transfer one or more therapeutic composition(s) across a surface of the eyeball, while the passive electrode serves as a return electrode and enables the electric circuit to be looped through the patient's body. The compound of interest is transported via the active electrode across the tissue when a current is applied to the electrodes through the tissue. Compound transport may occur as a result of a direct electrical field effect (e.g., electrorepulsion), an indirect electrical field effect resulted from the bulk volume flow of solution from the anode to cathode (e.g., electro-osmosis), electrically induced pore or transport pathway formation (e.g., electroporation), or a combination of any of the foregoing. Examples of currently known iontophoretic devices and methods for ocular drug delivery may be found in the U.S. Pat. Nos. 7,164,943; 6,697,668; 6,319,240; 6,539,251; 6,579,276; 6,697,668, and PCT publications WO 03/030989 and WO 03/043689, each of which is incorporated herein by reference.
Ocular iontophoresis, however, presents several unique challenges. For example, the applicator must conform to the spheroidal geometry of the eyeball. That is, the portion of the applicator in contact with a surface of the eye must be specifically formed to minimize loss of therapeutic composition and to reduce discomfort. Also, since the electrical impedance of the eye is relatively lower than that of the epidermis, higher currents can be achieved at still reasonably low current densities. Accordingly, dosage times tend to be relatively short, often much less than one hour.
Furthermore, iontophoretic transfer of a therapeutic composition with an inert electrode may result in unwanted changes in pH that result in patient discomfort, and in some instances, tissue damage. There remains a need to regulate the pH of a therapeutic preparation within the physiologically acceptable range during iontophoresis while maintaining the therapeutic composition at the highest ionization state for optimal delivery. Further, there remains a need to improve the delivery efficiency of a therapeutic composition while reducing the risks of any possible damage (e.g., irritation or burning of tissues) that could limit the use of ocular iontophoresis.